HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.
HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.
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DOI：
10.1038/s41598-023-33889-3
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发表时间：
2023-08-01
影响因子：
4.6
通讯作者：
中科院分区：
文献类型：
--
作者：
低级别和继发性高级别神经胶质瘤经常包含IDH 1或IDH 2代谢酶的突变，假设这些突变通过抑制许多调节DNA结构的染色质调节酶来驱动肿瘤发生。组蛋白去乙酰化酶抑制剂是一种很有前途的抗肿瘤药物，已经用于临床试验。然而，对它们的机制或基因靶点缺乏明确的了解。在这项研究中，作者从基因上解剖了患者来源的IDH 1突变培养物，以确定哪些HDAC酶驱动IDH 1突变胶质瘤的生长。对一组患者来源的胶质瘤球细胞系（2个IDH 1突变系，3个IDH 1野生型系）进行来自不同表观遗传类别的表观遗传修饰药物的药物筛选。LBH（帕比司他）对基因表达和染色质结构的影响在患者来源的IDH 1突变株系上进行测试。使用慢病毒RNA干扰敲低载体和胶质母细胞瘤（HK 252）的患者来源的IDH 1突变体体外模型，从分子上剖析了每种高表达HDAC酶的作用。然后在体内异种移植模型（BT-142）中证实了这些结果。IDH 1突变导致基因下调，DNA高甲基化，增加DNA可及性和H3 K27低乙酰化在两个不同的IDH 1突变过表达模型。药物筛选更具体地将组蛋白脱乙酰酶抑制剂（HDACi）和帕比司他（LBH）鉴定为抑制IDH 1突变神经胶质瘤系生长的最具选择性的化合物。在11种注释的HDAC酶（HDAC 1 -11）中，只有6种在IDH 1突变胶质瘤组织样品和患者来源的胶质瘤球体系（HDAC 1 -4、HDAC 6和HDAC 9）中表达。慢病毒敲低实验表明，HDAC 1和HDAC 6是体外和体内生长最必需的，并且靶向非常不同的基因模块。在体内敲低HDAC 1或HDAC 6导致更局限的侵袭性更低的肿瘤。IDH 1突变引起的基因失调是广泛存在的，并且通过直接IDH 1抑制仅部分可逆。这项研究确定HDAC 1和HDAC 6是重要的和药物靶向的酶，是IDH 1突变胶质瘤生长和侵袭所必需的。
Low-grade and secondary high-grade gliomas frequently contain mutations in the IDH1 or IDH2 metabolic enzymes that are hypothesized to drive tumorigenesis by inhibiting many of the chromatin-regulating enzymes that regulate DNA structure. Histone deacetylase inhibitors are promising anti-cancer agents and have already been used in clinical trials. However, a clear understanding of their mechanism or gene targets is lacking. In this study, the authors genetically dissect patient-derived IDH1 mutant cultures to determine which HDAC enzymes drive growth in IDH1 mutant gliomas. A panel of patient-derived gliomasphere cell lines (2 IDH1 mutant lines, 3 IDH1 wildtype lines) were subjected to a drug-screen of epigenetic modifying drugs from different epigenetic classes. The effect of LBH (panobinostat) on gene expression and chromatin structure was tested on patient-derived IDH1 mutant lines. The role of each of the highly expressed HDAC enzymes was molecularly dissected using lentiviral RNA interference knock-down vectors and a patient-derived IDH1 mutant in vitro model of glioblastoma (HK252). These results were then confirmed in an in vivo xenotransplant model (BT-142). The IDH1 mutation leads to gene down-regulation, DNA hypermethylation, increased DNA accessibility and H3K27 hypo-acetylation in two distinct IDH1 mutant over-expression models. The drug screen identified histone deacetylase inhibitors (HDACi) and panobinostat (LBH) more specifically as the most selective compounds to inhibit growth in IDH1 mutant glioma lines. Of the eleven annotated HDAC enzymes (HDAC1-11) only six are expressed in IDH1 mutant glioma tissue samples and patient-derived gliomasphere lines (HDAC1-4, HDAC6, and HDAC9). Lentiviral knock-down experiments revealed that HDAC1 and HDAC6 are the most consistently essential for growth both in vitro and in vivo and target very different gene modules. Knock-down of HDAC1 or HDAC6 in vivo led to a more circumscribed less invasive tumor. The gene dysregulation induced by the IDH1 mutation is wide-spread and only partially reversible by direct IDH1 inhibition. This study identifies HDAC1 and HDAC6 as important and drug-targetable enzymes that are necessary for growth and invasiveness in IDH1 mutant gliomas.
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影响因子：
64.8
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通讯作者：
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影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
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15.9
作者：
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通讯作者：
Shaw, Edward G.
影响因子：
158.5
作者：
DiNardo, C. D.;Stein, E. M.;Kantarjian, H. M.
通讯作者：
Kantarjian, H. M.
影响因子：
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作者：
Court, Franck;Le Boiteux, Elisa;Arnaud, Philippe
通讯作者：
Arnaud, Philippe